Program in Genetics and Genome Biology, SickKids Research Institute, Toronto, ON, Canada.
Department of Molecular Genetics, The University of Toronto, Toronto, ON, Canada.
Blood. 2020 Dec 3;136(23):2679-2690. doi: 10.1182/blood.2020005394.
Quebec platelet disorder (QPD) is an autosomal dominant bleeding disorder with a unique, platelet-dependent, gain-of-function defect in fibrinolysis, without systemic fibrinolysis. The hallmark feature of QPD is a >100-fold overexpression of PLAU, specifically in megakaryocytes. This overexpression leads to a >100-fold increase in platelet stores of urokinase plasminogen activator (PLAU/uPA); subsequent plasmin-mediated degradation of diverse α-granule proteins; and platelet-dependent, accelerated fibrinolysis. The causative mutation is a 78-kb tandem duplication of PLAU. How this duplication causes megakaryocyte-specific PLAU overexpression is unknown. To investigate the mechanism that causes QPD, we used epigenomic profiling, comparative genomics, and chromatin conformation capture approaches to study PLAU regulation in cultured megakaryocytes from participants with QPD and unaffected controls. QPD duplication led to ectopic interactions between PLAU and a conserved megakaryocyte enhancer found within the same topologically associating domain (TAD). Our results support a unique disease mechanism whereby the reorganization of sub-TAD genome architecture results in a dramatic, cell-type-specific blood disorder phenotype.
魁北克血小板疾病（QPD）是一种常染色体显性出血性疾病，具有独特的、依赖血小板的纤维蛋白溶解功能获得性缺陷，而无全身性纤维蛋白溶解。QPD 的显著特征是 PLAU 的过度表达超过 100 倍，特别是在巨核细胞中。这种过度表达导致血小板储存的尿激酶纤溶酶原激活物（PLAU/uPA）增加超过 100 倍；随后纤溶酶介导的各种α-颗粒蛋白降解；以及依赖血小板的加速纤维蛋白溶解。致病突变是 PLAU 的 78kb 串联重复。这种重复如何导致巨核细胞特异性 PLAU 过度表达尚不清楚。为了研究导致 QPD 的机制，我们使用表观基因组分析、比较基因组学和染色质构象捕获方法研究了来自 QPD 患者和未受影响对照者培养的巨核细胞中 PLAU 的调节。QPD 重复导致 PLAU 与在同一拓扑关联域（TAD）内发现的保守巨核细胞增强子之间的异位相互作用。我们的结果支持一种独特的疾病机制，即亚 TAD 基因组结构的重组导致明显的、细胞类型特异性的血液疾病表型。
